Regulation of nerve growth and patterning by cell surface protein disulphide isomerase
- University of Cambridge, United Kingdom
Abstract
Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in chick half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Medical Research Council
- Geoffrey MW Cook
- Roger J Keynes
Wellcome
- Geoffrey MW Cook
- Roger J Keynes
Spinal Research
- Julia Schaeffer
Trinity College, University of Cambridge
- Roger J Keynes
University of Cambridge
- Geoffrey MW Cook
- Catia Sousa
- Julia Schaeffer
- Katherine Wiles
- Prem Jareonsettasin
- Asanish Kalyanasundaram
- Eleanor Walder
- Catharina Casper
- Serena Patel
- Pei Wei Chua
- Gioia Riboni-Verri
- Mansoor Raza
- Nol Swaddiwudhipong
- Andrew Hui
- Ameer Abdullah
- Saj Wajed
- Roger J Keynes
Rosetrees Trust
- Geoffrey MW Cook
- Julia Schaeffer
- Roger J Keynes
The Anatomical Society
- Eleanor Walder
Amgen Foundation Summer Scholarship
- Gioia Riboni-Verri
The authors declare that the funders provided research equipment and laboratory consumables, as well as salary support for Julia Schaeffer, Eleanor Walder and Gioia Riboni-Verri.
Ethics
Animal experimentation: Chick embryos were used for this work, and all experiments were carried out at earlier developmental stages than those that require ethical approval.
Copyright
© 2020, Cook et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Regulation of nerve growth and patterning by cell surface protein disulphide isomerase
eLife 9:e54612.
https://doi.org/10.7554/eLife.54612
Further reading
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Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis causes multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically when organs are forming. While the pathway is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown. Here, we used a mouse model of human CNDD and assessed pathway functionality in embryonic livers and extraembryonic tissues via gene expression, enzyme activity and metabolic analyses. We found that the extra-embryonic visceral yolk sac endoderm exclusively synthesises NAD de novo during early organogenesis before the embryonic liver takes over this function. Under CNDD-inducing conditions, visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles, affecting embryo metabolism. Expression of requisite pathway genes is conserved in the equivalent yolk sac cell type in humans. Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryogenesis and its perturbation causes CNDD. As mouse and human yolk sacs are functionally homologous, our data improve the understanding of human congenital malformation causation.
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